1. Field Of The Invention
The present invention relates to a process for preparing 3-substituted methyl-3-cephem-4-carboxylic acids which are useful as intermediates for various cephalosporin antibiotics having a high antimicrobial activity across a broad antimicrobial spectrum. More particularly, the present invention is concerned with a process for preparing a 3-substituted methyl-3-cephem-4-carboxylic acid represented by formula (I) or a pharmaceutically acceptable salt thereof, ##STR1## wherein R.sup.1 represents a hydrogen atom or a lower alkoxy group and R.sup.2 represents an unsubstituted or substituted lower alkyl group or an unsubstituted or substituted aryl group, which can be carried out in one step and which can provide the desired product with high purity in high yield.
2. Discussion Of Related Art
As a process for preparing a 3-substituted methyl-3-cephem-4-carboxylic acid represented by formula (I) from a starting 3-acetoxymethyl-3-cephem-4-carboxylic acid represented by formula (II), ##STR2## wherein R.sup.1 represents a hydrogen atom or a lower alkoxy group, there have heretofore been proposed, for example, a method (1) in which the compound of formula (II) is reacted with a lower alcohol in the presence of a halide of an alkali metal, a halide of an alkaline earth metal or a halide of a quaternary ammonium (see U.S. Pat. No. 4,482,710), a method (2) in which the compound of formula (II) is reacted with a lower alcohol in the presence of boron trifluoride or a boron trifluoride complex (see European Patent Application Publication No. 204,657), a method (3) in which the compound of formula (II) is reacted a lower alcohol in the presence of an alkylsulfonic acid and a complex of boron trifluoride (see Japanese Patent Application Laid-Open Specification No. 63-115887), and a method (4) in which the compound of formula (II) is reacted with a lower alcohol in the presence of a halide of antimony, tin, iron, zinc or bismuth, or a complex thereof (see European Patent Application Publication No. 262,744).
However, none of the above-mentioned conventional methods, (1), (2), (3) and (4) can be satisfactorily practiced on a commercial scale.
According to method (1), the yield of the desired product is as low as, for example, 16 to 43%. In method (2), a lactone represented by the following formula, ##STR3## wherein R.sup.1 has the same meaning as defined above, is formed as a by-product in a large amount so that there is a cumbersome problem in isolation of the desired product. That is, for isolation of the desired product from the reaction mixture containing a large amount of a lactone, (i) a large amount of a solvent for extraction-separating the lactone and/or a plurality of steps for extraction-separating the lactone are required, (ii) an extremely large amount of a resin for the separation and purification of the desired product must be used, or (iii) treatment for the precipitation-separation of the desired product at its isoelectric point must be repeated many times. Therefore, method (2) is unsatisfactory as a practical matter. Particularly, when the amount of boron trifluoride or a boron trifluoride complex is increased to improve the yield of the desired product of formula (I), formation of the undesired lactone is increased. As a result, the purity of the desired product is lowered, and isolation of the desired product becomes very cumbersome, so that loss of the desired product during the isolation is likely to be large. In methods (3) and (4), formation of the undesired lactone is not sufficiently suppressed. Accordingly, these methods are not satisfactory in yield and purity of the desired product.
Further, in other conventional processes for preparing a 3-substituted methyl-3-cephem-4-carboxylic acid, for avoiding the side reactions at the carboxyl group of the starting material, it has inevitably been necesssary to protect the carboxyl group of the starting material by, for example, esterifying the carboxyl group of the starting material prior to the reaction with the reactant. The resultant ester can be easily deesterified and, after the reaction, the esterified carboxy group is deesterified to reinstate the carboxyl group, thereby obtaining the desired product.
Therefore, there has still been a strong demand in the art for an improved practical process for preparing a 3-substituted methyl-3-cephem-4-carboxylic acid represented by formula (I), which can be carried out in one step and can provide the desired product with high purity in high yield.